The chimera antigen receptor (CAR) T cell therapy is a novel and potential targeted therapy and has achieved satisfactory efficacy in patients with relapsed or refractory multiple myeloma (MM) in recent years. However, cytokine release syndrome (CRS) and clinical efficacy have become the major obstacles which limit the application of CAR-T in clinics. To explore the potential biomarkers in plasma for evaluating CRS and clinical efficacy, we performed metabolomic and lipidomic profiling of plasma samples from 17 relapsed or refractory MM patients received CAR-T therapy. Our study showed that glycerophosphocholine (GPC), an intermediate of platelet-activating factor (PAF)-like molecule, was significantly decreased when the participants underwent CRS, and the remarkable elevation of lysophosphatidylcholines (lysoPCs), which were catalyzed by lysoPC acyltransferase (LPCAT) was a distinct metabolism signature of relapsed or refractory MM patients with prognostic value post-CAR-T therapy. Both GPC and lysoPC are involved in platelet-activating factor (PAF) remodeling pathway. Besides, these findings were validated by LPCAT1 expression, a key factor in the PAF pathway, associated with poor outcome in three MM GEP datasets of MM. In conclusion, CAR-T therapy alters PAF synthesis in MM patients, and targeting PAF remodeling may be a promising strategy to enhance MM CAR-T therapy.

中文翻译：

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CAR-T疗法改变多发性骨髓瘤患者血小板活化因子的合成

嵌合抗原受体（CAR）T细胞疗法是一种新型的潜在靶向疗法，近年来在复发或难治性多发性骨髓瘤（MM）患者中取得了令人满意的疗效。然而，细胞因子释放综合征（CRS）和临床疗效已成为限制CAR-T临床应用的主要障碍。为了探索血浆中用于评估 CRS 和临床疗效的潜在生物标志物，我们对 17 名接受 CAR-T 治疗的复发或难治性 MM 患者的血浆样本进行了代谢组学和脂质组学分析。我们的研究表明，当参与者接受 CRS 时，血小板激活因子 (PAF) 样分子的中间体甘油磷酸胆碱 (GPC) 显着降低，溶血磷脂酰胆碱 (lysoPCs) 显着升高，由 lysoPC 酰基转移酶 (LPCAT) 催化的代谢特征是复发或难治性 MM 患者的独特代谢特征，具有 CAR-T 治疗后的预后价值。GPC 和 lysoPC 都参与血小板活化因子 (PAF) 重塑途径。此外，这些发现得到了 LPCAT1 表达的验证，LPCAT1 表达是 PAF 途径中的一个关键因素，与 MM 的三个 MM GEP 数据集中的不良结果相关。总之，CAR-T 治疗改变了 MM 患者的 PAF 合成，靶向 PAF 重塑可能是增强 MM CAR-T 治疗的有前景的策略。PAF 途径中的一个关键因素，与 MM 的三个 MM GEP 数据集的不良结果相关。总之，CAR-T 治疗改变了 MM 患者的 PAF 合成，靶向 PAF 重塑可能是增强 MM CAR-T 治疗的有前景的策略。PAF 途径中的一个关键因素，与 MM 的三个 MM GEP 数据集的不良结果相关。总之，CAR-T 治疗改变了 MM 患者的 PAF 合成，靶向 PAF 重塑可能是增强 MM CAR-T 治疗的有前景的策略。